Osteoporosis is estimated to affect 15-20 million people (both women and men) each year, causing significant morbidity and mortality. The widely used predictors of fracture risk are bone mineral density (BMD) and incidence of a previous fracture. One of the dilemmas in the management of osteoporosis is that two individuals with the same bone density and similar life-styles can show extensive diversity in their tendency to fracture. There is little information on what, other than differences in life style and fall severity, can account for this discrepancy. The underlying hypothesis of this grant is that discrete differences in mineral and matrix properties contribute to the altered fracture risk in these individuals. Over the past two funding periods, we have shown that Fourier transform infrared microspectroscopy (FTIRM) and imaging (FTIRI) provide reproducible and valuable information on the mineral and matrix properties of bone. We now wish to extend this approach to two new research questions: Aim 1) Do the mineral and matrix properties differ in biopsies from patients with fracture compared with patients without fractures while controlling for age, gender, bone mineral density, and architecture? This question will be tested by assessing biopsied specimens from individuals with different fracture histories and with known age, gender, and bone mineral density. MicroCT will be used to assess architecture of the specimens, and FTIR will be used to characterize mineral and matrix properties. Under this specific aim, we will also examine associations between FTIR parameters and nanoindentation in a subset of biopsies to establish the nanoindentation technique and to test for significant correlations between mineral/matrix properties and indentation modulus and hardness. We will also develop the use of imaging ATR to establish an IR approach that does not required thin sections of embedded bone. Aim 2) Do therapeutic agents reverse the observed alterations in mineral and matrix properties? Specifically we shall examine the relative effects of a SERM (selective estrogen receptor modulator), raloxifene, Hormone Replacement Therapy, and a bisphosphonate (Risedronate) on the mineral and matrix properties in pre- and post- therapy biopsies, to identify the agent(s) that reverse(s) the observed alterations in mineral and matrix properties. Emphasis will be placed on those properties identified in Aim 1 that are most predictive of fracture.